We hypothesize that the antioxidant deficient state generated by a dietary deficiency of selenium and/or vitamin E will enhance the induction of mammary carcinogenesis. If this is found to be the case, our goal is to define the mechanism(s) that accounts for the effect. The questions that will be addressed in this project are: 1. What is the effect of adequate versus deficient concentrations of dietary selenium and/or vitamin E on the process of mammary carcinogenesis; during what stage(s) of the carcinogenic process is an effect exerted; is the effect(s) modulated by the amount or type of dietary fat? 2. Does a dietary deficiency of selenium and/or vitamin E induce oxidant stress in the mammary gland, what is the nature of the oxidant stress, the damage it induces and the kinetics of its accumulation. 3. Does oxidant stress induce changes other than lipid peroxidation that may have relevance to carcinogenesis? For example, does oxidant stress alter DNA (base modifications or strand breaks), membrane associated activities (protein kinase C activity) and/or other markers of biological activity (ODC activity) that appear to be relevant to tumorigenesis? 4. Is the nature of induced damage (identified in answering question 3) similar if generated by either a selenium or vitamin E deficiency and does it correlate in magnitude with the degree of antioxidant deficiency that is induced? Mammary carcinogenesis will be induced by DMBA or MNU. Animals with be fed chemically-defined diets which are low or high in fat and adequate in essential fatty acids but which vary in their content of selenium and vitamin E. Selenium and vitamin E status will be monitored by the measurement of tissue selenium and vitamin E concentrations and by assessing tissue glutathione peroxidase and reductase activities. Tissue concentrations of total and oxidizing glutathione, cytosolic and mitochrondrial superoxide dimutase activity, and superoxide anion formation also will be assessed. Membrane peroxidation will be measured as lipid diene conjugation and chemiluminescence of subcellular fractions and the peroxidation potential of the tissue measured by the thiobarbituric acid method. Other evidence of radical mediated damage will be evaluated by assays of high molecular weight DNA for strand breaks and of hydrolyzed DNA for base modifications. Other biomarkers may be assessed depending on the outcome of the initial set of experiments.